Alzheimer's disease (AD) is one of the most common and debilitating neurodegenerative diseases of older Americans. Several treatments show promise in slowing the development of AD, but to be truly effective, they must be started before full-blown AD appears. The prodominate phase of AD produces symptoms of mild cognitive impairment (MCI), but an ideal test would detect signs of incipient AD even before the appearance of MCI. Some recent data supports the view that inflammatory processes are important to the development of AD. We implemented a new technique, called Multiphoton Detection (MPD) supporting a family of high sensitivity diagnostic tests. In this application, MPD is used in assays targeting cytokines and applied to inflammatory processes leading to AD. The current assays are not sensitive enough to reliably measure cytokines in serum. We will demonstrate that the proposed protocols are sensitive and practical enough to be used as blood based screening assays for mild cognitive impairment (MCI) and AD. The specific aims of the proposed studies are: Aim 1: Further improvement of sensitivity of immunoassays for TNF-alpha, IFN-gamma, IL-1 beta and IL-6 Aim 2: Development of sub-pg/ml assay for IL-18 Aim 3: Optimization of ultrasensitive, CSF based assays of cytokines Aim 4: Validation of this assay by testing serum from MCI/AD patients and healthy controls.